Abstract The major effort in our lab has been to develop and translate novel therapies to prevent and reverse adverse immune repsonses, with the ultimate goal of clinical translation, for example, in monogenic diseases like hemophilia A (HA), but also in autoimmunity and allergy. These tolerogenic approaches include B-cell delivery of Fc-fusion proteins and nanoparticles that we have shown can lead to the activation of antigen-specific regulatory T cells (Tregs). During the last four years, our focus in HA has emphasized the production and validation of novel engineered specific regulatory T cells that express either a FVIII-specific T-cell receptor (TCR) or a single chain variable fragment (scFv) chimeric receptor (Kim et al., 2015, Yoon et al. 2017). The TCR-transduced Tregs are MHC-restricted and recognize FVIII-peptide on antigen-presenting cells. On the other hand, scFv-expressing Tregs (CAR-like) respond to conformational epitopes on cell surfaces. Recently, we developed an additional approach to inhibit/kill the FVIII-specific B-cells that give rise to plasma cells, using both Tregs and CD8+ T cells that express FVIII domains (Zhang et al. 2018). We named the latter cells ?BAR? for B-cell-targeting Antibody Receptor. The latter T cells express a chimeric receptor (CAR), comprised of a protein antigen or its domain, linked with the transmembrane and signal transduction domains, CD28-CD3?, like the above two CARs. The three types of engineered chimeric receptor T cells can strongly block the anti- FVIII immune response in vitro and in vivo, and recent data suggest that BAR Tregs can suppress the symptoms of anaphylaxis in the presence of circulating antibody. Based on the success of our approaches, our goals in this renewal are to further analyze and optimize the ability of these different engineered Tregs to suppress not only primary but also ongoing anti-FVIII responses in vitro and in vivo. We will also analyze the cellular targets and molecular mechanisms by which these engineered T cells suppress specific antibody formation in hemophilic mice as well as in B-cell receptor transgenics. Evaluating their long-term efficacy in vivo in the presence of circulating antibody is an important goal. These studies will provide proof of principle for the utility and mechanism of action of engineered Tregs and provide steps for clinical translation.